Substituted heteroarylamide oxazepinopyrimidone derivatives

ABSTRACT

The disclosure relates to a series pyrimidone derivatives represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: 
                         
wherein:
     Y, Z, R1, R2, R3, R4 and n are as defined in the disclosure. Also disclosed are methods of preparing the compounds of formula (I), intermediates therefor and their utility in treating a variety of disease conditions.

This application is a continuation of PCT/IB2009/000293,filed Jan.27,2009.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as p53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseasesand other pathologies where GSK3β is deregulated (Nature reviews Vol. 3,June 2004, p. 479-487; Trends in Pharmacological Sciences Vol. 25 No. 9,September 2004, p. 471-480; Journal of neurochemistry 2004, 89,1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384, 2002).

The neurodegenerative diseases include, in a non-limiting manner,Parkinson's disease, tauopathies (e.g. Fronto temporal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy), Wilson's disease, Huntington's disease (The Journal ofbiological chemistry Vol. 277, No. 37, Issue of September 13, pp.33791-33798, 2002), Prion disease (Biochem. J. 372, p. 129-136, 2003)and other dementia including vascular dementia; acute stroke and othertraumatic injuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis (European Journal of Neuroscience, Vol. 22, pp. 301-309, 2005)peripheral neuropathies; retinopathies and glaucoma. Recent studies havealso shown that inhibition of GSK3β results in neuronal differentiationof embryonic stem cells (ESC) and support the renewal of human and mouseESCs and the maintenance of their pluripotency. This suggests thatinhibitors of GSK3β could have applications in regenerative medicine(Nature Medicine 10, p. 55-63, 2004).

Inhibitors of GSK3β may also find application in the treatment of othernervous system disorders, such as bipolar disorders (manic-depressiveillness). For example lithium has been used for more than 50 years as amood stabiliser and the primary treatment for bipolar disorder. Thetherapeutic actions of lithium are observed at doses (1-2 mM) where itis a direct inhibitor of GSK3β. Although the mechanism of action oflithium is unclear, inhibitors of GSK3β could be used to mimic the moodstabilising effects of lithium. Alterations in Akt-GSK3β signaling havealso been implicated in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3β could be useful in treating cancers,such as colorectal, prostate, breast, non-small cell lung carcinoma,thyroid cancer, T or B-cell leukaemia and several virus-induced tumours.For example, the active form of GSK3β has been shown to be elevated inthe tumors of colorectal cancer patients and inhibition of GSK3β incolorectal cancer cells activates p53-dependent apoptosis andantagonises tumor growth. Inhibition of GSK3β also enhancesTRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also playsa role in the dynamics of the mitotic spindle and inhibitors of GSK3βprevent chromosome movement and lead to a stabilisation of microtubulesand a prometaphase-like arrest that is similar to that observed with lowdoses of Taxol. Other possible applications for GSK3β inhibitors includetherapy for non-insulin dependent diabetes (such as diabetes type II),obesity and alopecia.

Inhibitors of human GSK3β may also inhibit pfGSK3, an ortholog of thisenzyme found in Plasmodium falciparum, as a consequence they could beused for the treatment of malaria (Biochimica et Biophysica Acta 1697,181-196, 2004). Recently, both human genetics and animal studies havepointed out the role of Wnt/LPR5 pathway as a major regulator of bonemass accrual. Inhibition of GSK3β leads to the consequent activation ofcanonical Wnt signalling. Because deficient Wnt signalling has beenimplicated in disorders of reduced bone mass, GSK3β inhibitors may alsobe used for treating disorders of reduced bone mass, bone-relatedpathologies, osteoporosis.

According to recent data, GSK3β inhibitors might be used in thetreatment or prevention of Pemphigus vulgaris.

Recent studies show that GSK3beta inhibitor treatment improvesneutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitorswill be useful for the treatment of neutropenia induced by cancerchemotherapy.

Previous studies have shown that GSK3 activity decreases LTP, aelectrophysiological correlate of memory consolidation, suggesting thatinhibitor of this enzyme may have procognitive activity. Procognitiveeffects of the compound could find application for the treatment ofmemory deficits characteristic of Alzheimer's disease, Parkinsondisease, age-associated memory impairment, mild cognitive impairment,brain trauma, schizophrenia and other conditions in which such deficitsare observed.

Inhibitors of GSK3β may also find application in the treatment ofparenchymal renal diseases (Nelson P J, Kidney International Advanceonline publication 19 dec 2007) and in the prevention or treatment ofmuscle atrophy (J. Biol. Chem. (283) 2008, 358-366).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides as an object of the invention thepyrimidone derivatives represented by formula (I) or salts thereof,solvates thereof or hydrates thereof:

wherein:

-   Y represents two hydrogen atoms, a sulphur atom, an oxygen atom or a    C₁₋₂ alkyl group and a hydrogen atom;-   Z represents a bond, an oxygen atom, a nitrogen atom substituted by    a hydrogen atom or a C₁₋₃ alkyl group, a sulphur atom, a methylene    group optionally substituted by one or two groups chosen from a C₁₋₆    alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂    perhalogenated alkyl group or an amino group;-   R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine    ring, the ring being optionally substituted by a C₁₋₆ alkyl group, a    C₁₋₆ alkoxy group or a halogen atom;-   R2 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;-   R3 represents a 4-15 membered heterocyclic group, this group being    optionally substituted by 1 to 4 substituents selected from a C₁₋₆    alkyl group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a    C₁₋₆ halogenated alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group,    a C₁₋₆ halogenated alkoxy group, a nitro, a cyano, an amino, a C₁₋₆    monoalkylamino group, a C₂₋₁₂ dialkylamino group, a S—(C₁₋₆-alkyl)    group, a C(O)O(C₁₋₆-alkyl) or a C(O)O (aryl) group, an 4-15 membered    heterocyclic group, an aryl group, a O-aryl group or a S-aryl group,    the above-mentioned groups being optionally substituted by 1 to 4    substituents selected from a C₁₋₆ alkyl group, a halogen atom, a    (C₁₋₆) alkoxy group, a C(O)O (C₁₋₆-alkyl) or a C(O)O (aryl) group;-   R4 represents a hydrogen atom or a C₁₋₆ alkyl group; and-   n represents 0 to 3.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as: Non-insulin dependentdiabetes (such as diabetes type II) and obesity; malaria, bipolardisorders (manic depressive illness); schizophrenia; alopecia or cancerssuch as colorectal, prostate, breast cancer, non-small cell lungcarcinoma, thyroid cancer, T or B-cell leukaemia, several virus-inducedtumours and bone related pathologies; the treatment of parenchymal renaldiseases and in the prevention or treatment of muscle atrophy; thetreatment of cognitive and memory deficit. The medicament could alsofind an application in regenerative medicine.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the diseases are neurodegenerativediseases and are selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, tauopathies (e.g. Fronto temporaldementia, corticobasal degeneration, Pick's disease, progressivesupranuclear palsy), Wilson's disease, Huntington's disease, Priondisease and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis; peripheral neuropathies; retinopathies and glaucoma, and theaforementioned medicament in the form of pharmaceutical compositioncontaining the above substance as an active ingredient together with oneor more pharmaceutical additives.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the bones related pathologies areosteoporosis.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and the saltsthereof, and the solvates thereof and the hydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedor cycloalkyl group having 1 to 6 carbon atoms, optionally substitutedby a straight, branched or cyclic C₁₋₆ alkyl group, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexylgroup, isohexyl group, cyclopropylmethyl group and the like.

The 4-15 membered heterocyclic group represents an unsaturated, fullysaturated or partially saturated mono- or polycyclic group (for example4 to 10 members) containing one to seven heteroatoms chosen from N, O,and S. Examples of heterocyclic groups include pyridine, pyrindine,pyrimidine, pyrazine, pyridazine, triazine, pyrrole, furan, thiophene,pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole,oxadiazole, thiazole, isothiazole, thiadiazole, pyrrolopyrrole,pyrroloimidazole, pyrrolopyrazole, pyrrolotriazole, imidazoimidazole,imidazopyrazole, imidazotriazole, quinoline, isoquinoline, cinnoline,phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine,pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine,pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine,pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine,pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine, indole,isoindole, benzimidazole, indazole, indolizine, benzofuran,isobenzofuran, benzothiophene, benzo[c]thiophene, pyrrolopyridine,imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine,pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine,triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine,imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine,pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine,triazolopyridazine, tetrazolopyridazine, pyrrolotriazine,imidazotriazine, pyrazolotriazine, triazolotriazine, tetrazolotriazine,furopyridine, furopyrimidine, furopyrazine, furopyridazine,furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine,oxazolopyridazine, oxazolotriazine, isoxazolopyridine,isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine,isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine,oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine,benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine,thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine,thiazolopyridine, thiazolopyrimidine, thiazolopyrazine,thiazolopyridazine, thiazolotriazine, isothiazolopyridine,isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine,isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine,thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine,benzothiazole, benzoisothiazole, benzothiadiazole, benzotriazole,benzodioxepine, benzodioxane, benzodioxine, diazepane. Theseheterocycles can exist also in a partially or fully saturated form, forexample as an illustration dihydrobenzofuran, tetrahydroquinoline etc. .. .

The C₁₋₆ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen atoms have been substituted by a halogeno, for examplea CF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast, one hydrogen has not been substituted by a halogen atom;

The C₁₋₆ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group, isopentylamino groupand the like;

The C₂₋₁₂ dialkylamino group represents an amino group substituted bytwo C₁₋₆ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group and the like;

A leaving group L represents a group which could be easily cleaved andsubstituted; such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt.

Examples of the salt include, when an acidic group exists, salts ofalkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid; salts with organic acidssuch as acetic acid, propionic acid, tartaric acid, fumaric acid, maleicacid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acidand the like.

The acid-addition salts of the basic compounds are prepared by standardprocedures well known in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention.

The pyrimidone derivatives represented by the aforementioned formula (I)may have one or more asymmetric carbon atoms. As for the stereochemistryof such asymmetric carbon atoms, they may independently be either in (R)or (S) configuration, and the derivative may exist as stereoisomers suchas optical isomers, or diastereoisomers. Any stereoisomers in pure form,any mixtures of stereoisomers, racemates and the like fall within thescope of the present invention.

In a first embodiment of the invention, there is provided compoundswherein Z represents a bond, R1 represents an unsubstituted 4-pyridinering or unsubstituted 4-pyrimidine ring, R2 is hydrogen, R3 represents apyridine group, a pyrimidine group, a benzodioxin group, atetrahydroquinoline group, a tetrahydroisoquinoline group, anaphthyridin group, a benzofuran group, a pyridazine and these groupsbeing optionally substituted by 1 to 4 substituents selected from ahalogen atom, a C₁₋₆ alkoxy group, an amino, a S—(C₁₋₆-alkyl) group, an4-15 membered heterocyclic group, an aryl group, a O-aryl group or aS-aryl group, a C(O)O(C₁₋₆-alkyl) group; R4 represents hydrogen, Yrepresents O or two hydrogen atoms and n represents 0 in the form of afree base or of an addition salt with an acid.

Examples of compounds of the present invention are shown in table 1hereinafter. However, the scope of the present invention is not limitedby these compounds. The nomenclature is given according to IUPAC rules.

A further object of the present invention includes the group ofcompounds of table 1 of formula as defined hereunder:

-   1.    (+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-nicotinamide-   2.    (+/−)-7-(4-Oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid tert-butyl ester-   3.    (+/−)-6-(4-Oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid tert-butyl ester-   4. (+/+[1,5]Naphthyridine-2-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   5. (+/−)-6-Methoxy-pyridine-2-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   6. (—F0-4-Methoxy-pyridine-2-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   7. (+/−)-1,2,3,4-Tetrahydro-isoquinoline-7-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   8. (+/−)-5-Bromo-2,3-dihydro-benzofuran-7-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   9. (+/−)-1,2,3,4-Tetrahydro-isoquinoline-6-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   10.    (+/−)-8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic    acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   11.    (+/−)-2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-nicotinamide-   12. (+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   13. (+/−)-2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   14. (+/−)-3,6-Dimethoxy-pyridazine-4-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   15. (+/−)-5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   16. (+/−)-2,3-Dihydro-benzofuran-7-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   17. (+/−)-Pyridine-2-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   18. (+/−)-5-Bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid    (4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   19.    (+/−)-9-[(Pyridin-2-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one-   20. (+/−)-Pyridine-2-carboxylic acid    (4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   21. (+/−)-4-Methoxy-pyridine-2-carboxylic acid    (4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide-   22.    (+/−)-2,6-Dimethoxy-N-(4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-nicotinamide-   23.    (+/−)-9-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one-   24.    (+/−)-9-[(Benzo[1,3]dioxol-4-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one-   25.    (+/−)-9-[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

As a further object, the present invention concerns also methods forpreparing the pyrimidone compounds represented by the aforementionedformula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Pyrimidone compounds represented by the aforementioned formula (I), maybe prepared according to the method described in the scheme 1.

(In the above scheme the definition of R1, R2, R3, R4, n, Y and Z arethe same as those already described for compound of formula (I)).

Following this method, the pyrimidone derivative represented by theabove formula (III), wherein R1, R2 and R4, are as defined for compoundsof formula (I), are used as intermediates. Alternatively compounds offormula (I) are allowed to react with a base such as triethylamine,sodium carbonate or potassium carbonate in a solvent such astetrahydrofuran, N-methylpyrrolidone, N,N-dimethylacetamide orchloroform at a suitable temperature ranging from 0 to 130° C. underordinary air, then with a compound of formula (II), wherein R3, Z, Y andn are as defined for compound of formula (I) and L represents a leavinggroup preferably chlorine, bromide or mesyl group, to obtain thecompound of the aforementioned formula (I).

Alternatively compounds of formula (I) wherein Y represents two hydrogenatoms may be prepared by reductive amination of a compound of formula(II) wherein Y represents an oxygen atom and L represents a hydrogenatom, by a compound of formula (III) wherein R1, R2 and R4 are asdefined for compound of formula (I), according to well known methods toone skilled in the art.

Compound of formula (II) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

Compound of formula (III) may be prepared according to the methoddefined in scheme 2, starting from compound of formula (IV). Theconditions which may be used are given in the chemical examples.

As a further object, the present invention concerns also intermediates(III), (VI) and (VII) for preparing the pyrimidone compounds representedby the aforementioned formula (I).

(In the above scheme the definitions of R1 and R2 are the same asalready described.)

According to this method, the 3-ketoester of formula (IV), wherein R1and R2 are as defined for compound of formula (I), R is an alkyl groupsuch as for example methyl or ethyl, is allowed to react with a compoundof formula (V). The reaction may be carried out in the presence of abase such as potassium carbonate, in an alcoholic solvent such asmethanol, ethanol and the like or without, at a suitable temperatureranging from 25° to 140° C. under ordinary air to obtain the compound ofthe aforementioned formula (VI).

The compound of formula (VI) wherein R1 and R2 are as defined forcompound of formula (I) can be deprotonated with strong base (such aslithium bis(trimethylsilyl)amide or lithium diisopropyl amide) and theresultant anion reacted with bromine or N-bromosuccinimide to afford thecompound of formula (VII).

The compound of formula (VII), wherein R1 and R2 are as defined forcompound of formula (I), can react with suitable nucleophilic nitrogensources such as ammonia, 4-methoxybenzylamine to afford the compound offormula (III).

Additionally compound of formula (III) wherein R2 represents a hydrogenatom may be halogenated in order to give compounds of formula (III),wherein R2 is a halogen atom such as a bromine atom or a chlorine atom.The reaction may be carried out in an acidic medium such as acetic acidor propionic acid, in presence of bromosuccinimide, chlorosuccimide orbromine.

In addition, compounds of formula (IV), wherein R2 represents a fluorineatom, may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, No. 45, pp 6113-6116, 1989.

In addition, compounds of formula (IV) wherein R2 represents a hydrogenatom may be obtained by analogy to the method described in patent DE2705582.

Compound of formula (IV) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

For example compounds of formula (IV), wherein R1 represents a pyridinering or a pyrimidine ring, optionally substituted by a C₁₋₆ alkyl group,C₁₋₆ alkoxy group or a halogen atom, can be prepared by reactingrespectively an isonicotinic acid or a pyrimidine-carboxylic acid,optionally substituted by a C₁₋₆ alkyl group, C₁₋₆ alkoxy group or ahalogen, with the corresponding malonic acid monoester. The reaction canbe carried out using methods well known to one skilled in the art, suchas for example in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

Compound of formula (V) may be synthesized according to the methoddescribed in WO97/16430 and Bioorganic & Medicinal Chemistry Letters(2004), 14(23), 5907-5911.

In the above reactions protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Greene'sProtective Groups in Organic Synthesis, Greene et al., 4th Ed. (JohnWiley & Sons, Inc., New York) 2007.

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. Fronto temporal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy), Wilson's disease, Huntington'sdisease, Prion disease and other dementia including vascular dementia;acute stroke and others traumatic injuries; cerebrovascular accidents(e.g. age related macular degeneration); brain and spinal cord trauma;amyotrophic lateral sclerosis, peripheral neuropathies; retinopathiesand glaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; malaria, manic depressiveillness; schizophrenia; alopecia; cancers such as colorectal, prostatebreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia, several virus-induced tumours and in bone relatedpathologies; parenchymal renal diseases or muscle atrophy. Themedicament could also find an application in regenerative medicine. Themedicament could also find an application in the treatment or preventionof Pemphigus vulgaris. The medicament could also find an application inthe treatment of neutropenia induced by cancer chemotherapy. Themedicament could also find an application for therapeutic treatment of adisease characterized by cognitive and memory deficits such as inAlzheimer's disease, Parkinson disease, age associated memoryimpairment, mild cognitive impairment, brain trauma, schizophrenia andother conditions in which such deficits are observed.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention; however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES Example 1 Compound No. 2 of Table 1(+/−)-7-(4-Oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester 1.12-Pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

To a suspension of 25.00 g (165.99 mmol) of2,3,6,7-tetrahydro-[1,4]oxazepin-5-ylamine monohydrochloride (synthesisas described in WO97/16430 and Bioorganic & Medicinal Chemistry Letters(2004), 14(23), 5907-5911) in 550 mL of ethanol was added 25.23 g(182.59 mmol) of potassium carbonate. The reaction mixture was stirredat room temperature for 10 min, 35.45 g (182.59 mmol) of ethyl3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixturewas stirred under reflux for 4 hours. The cooled solution was evaporatedto remove solvent. The mixture was dissolved with water and diethylether. After stirring, the resulting solid was filtered, washed withwater and diethyl ether to afford 21.7 g (53%) of the desired compoundas a powder.

NMR ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.32 (s, 1H), 9.04 (d, 1H), 8.22 (d, 1H), 7.28 (s, 1H), 4.48(m, 2H), 3.88 (m, 2H), 3.80 (m, 2H), 3.31 (m, 2H).

1.2(+/−)-9-Bromo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

To a solution of 5.00 g (20.47 mmol) ofpyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-onein dry tetrahydrofuran (200 mL) under argon at −40° C. was added 22.52mL (22.52 mmol) of lithium bis(trimethylsilyl)amide (1M intetrahydrofuran). The solution was stirred at −40° C. for 10 min and1.10 mL (21.49 mmol) of bromine was added rapidly. The reaction wasstirred at −40° C. during 20 minutes and the reaction mixture wasquenched with the addition of a saturated solution of ammonium chlorideand extracted with ethyl acetate. The organic phase was washed withsaturated sodium chloride solution and dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography(cyclohexane/ethyl acetate: 80/20 to 70/30) to afford 2.18 g (33%) ofproduct.

Mp: 176-178° C.

NMR ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.35 (s, 1H), 9.08 (d, 1H), 8.28 (d, 1H), 7.32 (s, 1H), 5.60(m, 1H), 5.18 (m, 1H), 4.21-4.01 (m, 4H), 3.68 (m, 1H).

1.3(+/−)-9-Amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

A suspension of 18.7 g (57.89 mmol) of(+/−)-9-bromo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-onein 520 mL of ammonia (7N solution in MeOH) in sealed tubes was stirredat 100° C. for 4 hours. The cooled solution was evaporated to removesolvent. After an acido-basic work-up and extraction withdichloromethane, the mixture was washed with saturated solution ofsodium chloride. The organic phase was dried over sodium sulfate andconcentrated. The residue was organised in diethyl ether to afford 6.70g (44%) of product as a yellow solid.

Mp: 149-141° C.

NMR ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.38 (s, 1H), 9.08 (d, 1H), 8.42 (d, 1H), 7.30 (s, 1H), 4.91(m, 1H), 4.41 (m, 1H), 4.20 (m, 1H), 3.90 (m, 2H), 3.61 (m, 2H), 2.38(br s, 2H).

1.4(+/−)-7-(4-Oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of 0.080 g (0.31 mmol) of(+/−)-9-Amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-onedissolved in 2.60 mL of dimethylformamide was added 0.086 g (0.31 mmol)of 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butyl ester.To the resulting mixture was added 60 μL (0.37 mmol) of diethylcyanophosphonate and 40 μL (0.31 mmol) of triethylamine at 0° C. Theresulting mixture was stirred at room temperature for 15 hours. Waterand ethyl acetate were added and the mixture was stirred. The resultingresidue was filtered, washed with water, ethyl acetate and diethyl etherto afford 0.062 g (38%) of the pure product as a white powder.

Mp: 252-254° C.

NMR ¹H (DMSO; 400 MHz)

δ (ppm): 9.37 (s, 1H), 9.01 (d, 1H), 8.88 (d, 1H), 8.25 (d, 1H), 7.85(s, 1H), 7.79 (d, 1H), 7.39 (d, 1H), 7.32 (s, 1H), 5.68 (m, 1H), 5.07(m, 1H), 4.65 (m, 2H), 4.18 (m, 1H), 4.08 (m, 2H), 3.88 (m, 1H), 3.62(m, 3H), 2.90 (m, 2H), 1.48 (s, 9H).

Example 2 Compound No. 7 of Table 11,2,3,4-Tetrahydro-isoquinoline-7-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amidehydrochloride (1: 1)

To a solution of 0.049 g (0.10 mmol) of(+/−)-7-(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (example 1) dissolved in 0.5 mL of dichloromethanewas added 0.24 mL (0.96 mmol) of hydrochloric acid (4M in dioxane). Theresulting mixture was stirred at room temperature for 2.5 hours. Theresulting residue was filtered, washed with dichloromethane andisopropylether to afford 0.031 g (70%) of the pure product as a yellowpowder.

Mp: 239° C. (dec.)

NMR ¹H (DMSO; 400 MHz)

δ (ppm): 9.38 (s, 1H), 9.04 (d, 1H), 8.92 (d, 1H), 8.20 (d, 1H), 7.92(d, 1H), 7.86 (s, 1H), 7.42 (d, 1H), 7.31 (s, 1H), 5.68 (m, 1H), 5.08(m, 1H), 4.41-4.05 (m, 5H), 3.91 (m, 1H), 3.65 (m, 1H), 3.45 (m, 2H),3.15 (m, 2H).

Example 3 Compound No. 19 of Table 1 (+/−)9-[(Pyridin-2-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

To a solution of 0.090 g (0.35 mmol) of(+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-onein 3.5 ml of dichloromethane was added 0.030 mL (0.36 mmol) of2-pyridine carboxaldehyde, 0.184 g (0.87 mmol) of sodiumtriacetoxyborohydride and few drops of glacial acetic acid. The reactionmixture was stirred at room temperature for 15 hours. The residue wasdissolved in dichloromethane and a saturated aqueous solution of sodiumcarbonate, extracted with dichloromethane and washed with saturatedaqueous solution of sodium chloride, dried over sodium sulfate andevaporated. A recrystallization in isopropanol gives 0.042 g (35%) ofpure product.

Mp: 162-164° C.

NMR ¹H (DMSO; 400 MHz)

δ (ppm): 9.38 (m, 1H), 9.08 (m, 1H), 8.54 (m, 1H), 8.40 (m, 1H), 7.75(m, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 4.85 (m, 1H), 4.48 (m, 1H), 4.30(m, 1H), 4.05 (m, 3H), 3.85 (m, 3H), 3.58 (m, 1H).

Example 4 Compound No. 20 of Table 1 (+/−)-Pyridine-2-carboxylic acid(4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide4.12-Pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

By analogy with the method described in example 1 (step 1.1), using3-oxo-3-pyridin-4-yl-propionic acid ethyl ester in place of ethyl3-(4-pyrimidinyl)-3-oxopropionate, 10.40 g (51%) of the compound wasobtained as a powder.

Mp: 156-159° C.

NMR ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 8.71 (d, 2H), 8.00 (d, 2H), 7.28 (s, 1H), 4.49 (m, 2H), 3.90(m, 2H), 3.80 (m, 2H), 3.35 (m, 2H).

4.2 (+/−)9-Amino-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one

By analogy with the method described in example 1 (step 1.2), using2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-onein place of2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one,the compound was obtained as a powder and used as such in the next step.To a suspension of 5.29 g (16.44 mmol) of9-bromo-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-onein 164 mL of toluene was added 4.51 g (32.88 mmol) of4-methoxybenzylamine and 7.01 mL (98.64 mmol) of dimethylsulfoxide. Thereaction mixture was stirred at 85° C. for 15 hours. The cooled solutionwas evaporated to remove solvent. The mixture was quenched with theaddition of a saturated solution of ammonium chloride and extracted withdichloromethane, washed with saturated solution of sodium chloride. Theorganic phase was dried over sodium sulphate and concentrated. The crudeproduct was purified by chromatography on silica gel eluting withdichloromethane and then, with a mixture ofdichloromethane/methanol/aqueous ammonia solution (29%) in theproportions 97/3/0.3 to give 2.00 g of product. The compound wasobtained as a powder and used as such in the next step.

To a solution of 2.00 g (1.32 mmol) of9-(4-methoxy-benzylamino)-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-onein acetonitrile/water (20/10 mL) was added 2.17 g (3.96 mmol) ofammonium cerium nitrate. The reaction was stirred at room temperaturefor 15 hours. After an acido-basic work-up and extraction withdichloromethane, the organic phase was washed with a saturated solutionof sodium chloride, dried over sodium sulphate and concentrated. Thecrude product was purified by chromatography on silica gel eluting witha mixture of dichloromethane/methanol/aqueous ammonia solution (29%) inthe proportions 98/2/0.2 to give 0.226 g (5%, 3 steps) of product as awhite powder.

Mp: 155-157° C.

NMR ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 8.75 (d, 2H), 8.11 (d, 2H), 7.15 (s, 1H), 4.89 (m, 1H), 4.41(m, 1H), 4.18 (m, 1H), 3.90 (m, 2H), 3.60 (m, 2H), 2.73 (m, 2H).

4.3 (+/−)-Pyridine-2-carboxylic acid(4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4-a-diaza-benzocyclohepten-9-yl)-amide

By analogy with the method described in example 1 (step 1.4), using(+/−)9-amino-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-oneand 2-pyridine carboxylic acid in place of(+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-oneand 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butylester, the compound, 0.035 g (57%), was obtained as a white powder.

Mp: 287-289° C.

NMR ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.95 (br s, 1H), 8.90 (m, 1H), 8.85 (d, 2H), 8.20 (d, 2H), 8.10(m, 2H), 7.75 (m, 1H), 7.31 (s, 1H), 5.58 (m, 1H), 5.10 (m, 1H), 4.15(m, 2H), 4.08 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 1. The compounds have been prepared according to the methods ofthe examples. In the table, Me represents a methyl group, (Rot.)indicates the levorotatory or dextrorotatory properties of theenantiomeric compound, (dec.) indicates the decomposition of thecompound.

TABLE 1 No. Rot R3 Z R1 R4 R2 Y n Mp ° C. salt 1 (+/−)

bond

H H O 0 283- 285 Free base 2 (+/−)

bond

H H O 0 252- 254 Free base 3 (+/−)

bond

H H O 0 247- 248 Free base 4 (+/−)

bond

H H O 0 325- 335 Free base 5 (+/−)

bond

H H O 0 282- 284 Free base 6 (+/−)

bond

H H O 0 276- 278 Free base 7 (+/−)

bond

H H O 0 239 (dec.) HCl (1:1) 8 (+/−)

bond

H H O 0 275- 277 Free base 9 (+/−)

bond

H H O 0 204 (dec.) HCl (1:1) 10 (+/−)

bond

H H O 0 282- 284 Free base 11 (+/−)

bond

H H O 0 187- 189 Free base 12 (+/−)

bond

H H O 0 260 (dec.) Free base 13 (+/−)

bond

H H O 0 244- 246 Free base 14 (+/−)

bond

H H O 0 276 (dec.) Free base 15 (+/−)

bond

H H O 0 258- 260 Free base 16 (+/−)

bond

H H O 0 286- 288 Free base 17 (+/−)

bond

H H O 0 325- 327 Free base 18 (+/−)

bond

H H O 0 277- 279 Free base 19 (+/−)

bond

H H H, H 0 162- 164 Free base 20 (+/−)

bond

H H O 0 287- 289 Free base 21 (+/−)

bond

H H O 0 275- 277 Free base 22 (+/−)

bond

H H O 0 265- 267 Free base 23 (+/−)

bond

H H H, H 0 222- 224 HCl (1:1) 24 (+/−)

bond

H H H, H 0 247- 250 HCl (1:1) 25 (+/−)

bond

H H H, H 0 238 (dec.) HCl (1:1)

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Four different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm ³³P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta.

In a third protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01°)/0 Tween 20 buffer forone hour at room temperature in the presence of GSK3beta (total reactionvolume: 100 microliters).

In a fourth protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for 90minutes at room temperature in the presence of commercial GSK3beta(Millipore) (total reaction volume: 100 microliters).

Inhibitors were solubilised in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH. (Woodgett, J. R. (1989)Analytical Biochemistry 180, 237-241.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 are between 0.1 nanomolar to 3 micromolarconcentrations.

For example, on the protocol 4, the compound No. 12 of table 1 shows anIC₅₀ of 0.005 μM, the compound No. 15 of table 1 shows an IC₅₀ of 0.031μM, the compound No. 17 of table 1 shows an IC₅₀ of 0.015 μM, thecompound No. 18 of table 1 shows an IC₅₀ of 0.052 μM.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch100 mg Lactose 200 mg Magnesium stearate  4 mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg

(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

What is claimed is:
 1. A compound of formula (I):

wherein: Y represents two hydrogen atoms, a sulphur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; z represents a bond, anoxygen atom, a nitrogen atom substituted by a hydrogen atom or a C₁₋₃alkyl group, a sulphur atom, a methylene group optionally substituted byone or two groups chosen from a C₁₋₆ alkyl group, a hydroxyl group, aC₁₋₆ alkoxy group, a C₁₋₂ perhalogenated alkyl group or an amino group;R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring,the ring being optionally substituted by a C₁₋₆ alkyl group, a C₁₋₆alkoxy group or a halogen atom; R2 represents a hydrogen atom, a C₁₋₆alkyl group or a halogen atom; R3 represents a 4-15 memberedheterocyclic group, this group being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₂perhalogenated alkyl group, a C₁₋₆ halogenated alkyl group, a hydroxylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ halogenated alkoxy group, a nitro, acyano, an amino, a C₁₋₆ monoalkylamino group, C₁₋₁₂ dialkylamino group,a S—(C₁₋₆-alkyl) group, a C(O)O (C₁₋₆-alkyl) or a C(O)O (aryl) group, a4-15 membered heterocyclic group, an aryl group, a O-aryl group or aS-aryl group, the above-mentioned groups being optionally substituted by1 to 4 substituents selected from a C₁₋₆ alkyl group, a halogen atom, a(C₁₋₆) alkoxy group, a C(O)O (C₁₋₆-alkyl) or a C(O)O (aryl) group; R4represents a hydrogen atom or a C₁₋₆ alkyl group; and n represents 0 to3; or a salt thereof.
 2. The compound according to claim 1, wherein zrepresents a bond; R1 represents an unsubstituted 4-pyridine ring orunsubstituted 4-pyrimidine ring; R2 is hydrogen; R3 represents apyridine group, a pyrimidine group, a pyridazine group, a benzodioxingroup, a tetrahydroquinoline group, a tetrahydroisoquinoline group, anaphthyridin group, or a benzofuran group and these groups beingoptionally substituted by 1 to 4 substituents selected from a halogenatom, a C₁₋₆ alkoxy group, an amino, a S—(C₁₋₆-alkyl) group, a 4-15membered heterocyclic group, an aryl group, a O-aryl group or a S-arylgroup, a C(O)O (C₁₋₆-alkyl) group; R4 represents hydrogen; Y representsO or two hydrogen atoms; and n represents 0; or a salt thereof.
 3. Thecompound according to claim 1 selected from the group consisting of:(+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-nicotinamide;(+/−)-7-(4-Oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester;(+/−)-6-(4-Oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester; (+/−)-[1,5]Naphthyridine-2-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-6-Methoxy-pyridine-2-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-4-Methoxy-pyridine-2-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-1,2,3,4-Tetrahydro-isoquinoline-7-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-5-Bromo-2,3-dihydro-benzofuran-7-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-1,2,3,4-Tetrahydro-isoquinoline-6-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-nicotinamide;(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-3,6-Dimethoxy-pyridazine-4-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-2,3-Dihydro-benzofuran-7-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-Pyridine-2-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-5-Bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid(4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-9-[(Pyridin-2-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one;(+/−)-Pyridine-2-carboxylic acid(4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-4-Methoxy-pyridine-2-carboxylic acid(4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-amide;(+/−)-2,6-Dimethoxy-N-(4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-7-oxa-1,4a-diaza-benzocyclohepten-9-yl)-nicotinamide;(+/−)-9-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one;(+/−)-9-[(Benzo[1,3]dioxo1-4-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one;and(+/−)-9-[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one;or a salt thereof.
 4. A compound represented by formula (III), (VI) or(VII):

wherein: R1 and R2 are as defined for the compound of formula (I)according to claim
 1. 5. A pharmaceutical composition comprising acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof and at least one pharmaceutical additive.
 6. Apharmaceutical composition comprising a compound of formula (I)according to claim 2 or a pharmaceutically acceptable salt thereof andat least one pharmaceutical additive.
 7. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 3 or apharmaceutically acceptable salt thereof and at least one pharmaceuticaladditive.
 8. A method of treating a neurodegenerative disease in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, wherein said neurodegenerativedisease is selected from the group consisting of Alzheimer's disease,Parkinson's disease, tauopathies, vascular dementia; acute stroke,traumatic injuries; cerebrovascular accidents, brain cord trauma, spinalcord trauma; peripheral neuropathies; retinopathies and glaucoma.
 9. Amethod of treating a disease in a patient, said disease selected fromthe group consisting of non-insulin dependent diabetes; obesity; manicdepressive illness; schizophrenia; and cancers; wherein said cancer isselected from the group consisting of breast cancer, non-small cell lungcarcinoma, thyroid cancer, T or B-cell leukemia and virus-inducedtumors; comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 10. A method of treatingmalaria in a patient, comprising administering to said patient atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 11. A methodof treating Pemphigus vulgaris in a patient, comprising administering tosaid patient a therapeutically effective amount of a compound of formula(I) according to claim 1 or a pharmaceutically acceptable salt thereof.12. A process for preparing a compound of formula (I) according to claim1 comprising: reacting a compound of formula (III):

with a compound of formula (II):

wherein R1, R2, R3, z, n, and Y are as defined in claim 1; and Lrepresents a leaving group.